ES2255103T3 - OSMOTIC DOSE ADMINISTRATION SYSTEM IN SOLUBLE FORM. - Google Patents

Abstract

Disclosed is an osmotic pharmaceutical delivery system comprising (a) a semipermeable wall that maintains its integrity during pharmaceutical delivery and which has at least one passage therethrough; (b) a single, homogeneous composition within said wall, which composition consists essentially of (i) a pharmaceutically active agent, (ii) at least one non-swelling solubilizing agent which enhances the solubility of the pharmaceutically active agent; (iii) at least one non-swelling osmotic agent and (iv) a non-swelling wicking agent dispersed throughout the composition which enhances the surface area contact of the pharmaceutical agent with the incoming aqueous fluid.

Description

Osmotic dose administration system in soluble form.

The present invention relates to the field of osmotic systems for pharmaceutical dose administration and preparations, particularly preparations that can administered orally

U.S. Pat. No. 3,916,899, of Theeuwes et al ., Describes a drug administration preparation that is said to release the pharmaceutical agent through openings in the wall of the tablet or capsule by means of the osmotic pressure differential that is established between the concentration of the pharmaceutical agent inside the tablet or capsule and the patient's external fluid medium when the medication is taken orally. See, also, US Pat. No. 3,845,770, from Theeuwes et al ., Which describes another preparation for administration by osmotic pressure differential of a pharmaceutical agent. In this original type of approach, the inside of the tablet had a hydrophobic core surrounded by a hydrophilic layer within the tablet wall. As such, the water entering the tablet remained in the hydrophilic layer and therefore, in reality, very little drug was released.

It has been believed that this approach did not administer the pharmaceutical agent as completely or effectively as previously believed previously. Therefore, a different approach was developed to release the pharmaceutical agent. In this approach, the interior of the tablet or capsule is characteristically two layers, one that contains the pharmaceutical agent (which will be released back to through the openings in the wall of the tablet or capsule) and the other being a layer of material that swells when entering contact with water. These materials that swell or expand to a steady state when exposed to water or other fluids Biological are called "osmopolymers." This is used volume expansion to physically force agent exit pharmacist through the openings that have formed in the wall, sheath or coating during manufacturing. The agent Pharmaceutical is mainly released as insoluble particles, which therefore have limited bioavailability. This has been called commonly the "push and pull" approach. See for example U.S. patents No. 5,422,123; 4,783,337; 4,765,989; 4,612,008; and 4,327,725. Patent literature has shown that this approach was necessary to administer the appropriate doses, at controlled speeds and for prolonged times, of great variety of drugs Other "systems have also been described. osmotic administration. "See, for example, patents from the USA No. 4,609,374; 4,036,228; 4,992,278; 4,160,020; Y 4,615,698. The osmopolymers in these types of systems are components whose functions are to swell when they interact with water and aqueous fluids. This swelling effect is defined in these patents as a property of embedding fluid so that it expands to a very high degree, usually showing a volume increase from 2 to 50 times.

Summary of the invention

Arriving at the present invention, it has been discovered that it is possible to effectively administer doses therapeutically effective, at controlled rates and during prolonged periods of time, of a wide variety of drugs without the need for polymers that swell or expand within the tablet wall so as to physically force the exit of the drug particles towards the desired use environment. Such as used herein, the term "bloat", that is, the property that the present invention has been able to avoid, it is used in a way that has the same definition as in the patents described above. In addition, the invention makes possible administering agents that have limited aqueous solubility. The present invention provides an osmotic system of Pharmaceutical administration according to claim 1.

According to the preferred invention, a osmotic system of administration, preferably in the form of a tablet, which dispenses a therapeutic agent that has a Limited water solubility or physiological environments without the use of osmopolymers or inflatable agents to administer the agents therapeutic In addition according to the present invention, the therapeutic agent in a composition that can solubilize the therapeutic agent by which the agent is administered therapeutic in a predominantly solubilized form.

In a preferred embodiment, the invention has combined appropriate solubilizing agents and, throughout the composition containing the agent (s) solubilizer (s) and the pharmaceutical (s), an agent "wick" effect that provides channels of increased flow for the pharmaceutical agent that has become predominantly in its solubilized form by means of the solubilizing agent (s), while still inside the tablet or capsule. Therefore, the drug is administered through passages in the covering wall by osmosis true predominantly in its solubilized form, more than by physical force on a particulate form.

Therefore, in one aspect, the invention provides an osmotic pharmaceutical administration system that comprises (a) a semipermeable wall that maintains its integrity during pharmaceutical administration and you have at least one passage through it; (b) a single homogeneous composition within said wall, composition containing (i) an agent pharmaceutically active, (ii) at least one non-solubilizing agent inflatable that increases the solubility of the agent pharmaceutically active, (iii) at least one non-inflatable osmotic agent and (iv) a non-inflatable wick effect agent dispersed throughout the composition which increases the contact of the surface area of the agent Pharmacist with the incoming aqueous fluid. Therefore the agent Pharmaceutical is released in a predominantly soluble form.

Preferred non-swelling solubilizing agents include (i) agents that inhibit the crystalline formation of pharmaceutical product or else they act by complexing with the same; (ii) an HLB micelle forming surfactant (balance hydrophilic-lipophilic) elevated, particularly nonionic and / or anionic surfactants; (iii) citrate esters; Y combinations thereof, particularly combinations of complexing agents with anionic surfactants. Agents Preferred non-inflatable osmotic include sugars with ten or less rings, preferably five or less rings and more preferably two rings. Examples include fructose, lactose, xylitol, and sorbitol. Preferred wicking agents include colloidal silicon dioxide and polyvinylpyrrolidone and lauryl sulfate Sodium can also function as wicking agents.

Brief description of the drawings

Now the invention will be further described. by reference to a brief description of each of the attached drawings. The brief description and drawings are not in in no way a limitation of the invention.

Figure 1A schematically illustrates the system osmotic technique of elementary dose administration previous.

Figure 1B schematically illustrates the system Osmotic dose administration of the prior art.

Figure 2 schematically illustrates the system Osmotic dose administration of the present invention.

Figure 3 schematically shows both percent of nifedipine released by pharmaceutical forms of the invention containing the 1G formulations (30 mg); 1C (30 mg); as shown in table 1 compared to Procardia XL® (Pfizer, Inc .; 30 mg).

Figure 4 schematically shows both percent of nifedipine released by pharmaceutical forms of the invention containing formulations 2B (47 mg); 2C (47 mg); Y 2D (47 mg) as shown in table 2, compared to Procardia XL® (Pfizer, Inc .; 30 mg).

Figure 5 schematically shows both percent of nifedipine released by pharmaceutical forms of the invention containing the 3C formulations (30 mg); 3H (30 mg); as shown in table 3, compared to Procardia XL® (Pfizer, Inc .; 30 mg).

Figure 6 schematically shows both percent of nifedipine released by forms of the invention that contain the formulations 4H (30 mg); 4C (90 mg); as it shown in table 4, compared to Procardia XL® (Pfizer, Inc .; 30 mg)

Figure 7 schematically shows both percent of nifedipine released by forms of the invention that contain the 5G formulations (60 mg); 5H (60 mg); as it shown in table 5, compared to Procardia XL® (Pfizer, Inc .; 60 mg)

Figure 8 schematically shows both percent of nifedipine released by forms of the invention that contain the formulations 6E (60 mg); 6F (60 mg); as it shown in table 6, compared to Procardia XL® (Pfizer, Inc., New York; 60 mg)

Figure 9 schematically shows both percent of nifedipine released by forms of the invention that contain the 6F formulation (60 mg) with a sealed coating of 1% ethyl cellulose as shown in table 6, in comparison with Procardia XL® (Pfizer, Inc., New York; 60 mg).

Detailed description of the preferred embodiments

The invention will now be described in more detail. in regards to the numerous embodiments and examples that They support it.

The semipermeable wall of the osmotic system of elemental administration consists of a polymeric material sprayed or sprayed on the tablet to give a weight of 2 - 15% coating. An example of a polymeric material, includes, but is not limited to, cellulose acetate. The use of such polymeric material requires plasticizers for greater flexibility, durability and stability. In the case of acetate cellulose, examples of suitable plasticizers are citrate of triethyl (TEC), propylene glycol (PG), a mixture of TEC and PG in ratios ranging from 25% of TEC plus 75% of PG up to 75% ECT plus 25% PG, Tween 80 or other esters of polyoxyethylene sorbitan, triacetin, diethyl phthalate, polyethylene glycol, mineral oil, tributyl sebacate, and glycerol. Plasticizers are included as a weight ratio of acetate cellulose suitable for creating a semipermeable wall for achieve retention of the bioactive substance while It allows the permeation of water to the tablet core.

The semipermeable tablet wall can contain at least one conduit that communicates the core content with the outside of the device, administering the drug beneficial through the ducts of the osmotic device elementary. The size of an individual duct can range from 100 microns to 1,000 microns, more preferred from 300 to 900 microns, what more preferred from 500 to 850 microns. They may be present one or multiple channels to communicate the content with the outside of the compressed.

A mecha effect agent, defined, is included like any material with the ability to extract water to the porous network of a management device in the core of this type of tablet formulation. A wicking agent can do this with or without swelling, but those used in the The present invention are non-inflatable wicks. Some materials can both drain water and swell, others They work only as wicking agents. Effect agents Wick are characterized by being able to experience fisisorción with water. Fisisorción is defined as a form of adsorption in which the Solvent molecules can adhere very rigidly to the wicking agent surfaces through interactions of van der Waals between the surface of the wick effect agent and the adsorbed molecule. In the case of a management device of drug, the adsorbed molecule is mainly water or other biological fluid that is mainly composed of water. An agent of wick effect that attracts water will ultimately have a volume which is essentially composed of the volume of the wicking agent and the volume of water attracted to him. A material that swells will have a volume that is essentially composed of the volume of the wick / inflatable effect agent, the volume of water attracted towards him, and an additional volume created by steric forces and molecular.

The wick effect agent included in the Formulations described in this invention create channels or pores in the tablet core This facilitates the channeling of molecules from water through the tablet core by fisisorción. The function of the wicking agent is to transport water to surfaces inside the tablet core, creating channels or an increased surface area network. For the purposes of this invention, these wicking agents do not swell in any appreciable grade. For bioactive agents with low solubility in water, the wicking agent helps in the administration of partially solubilized bioactive agent through the conduit in The semipermeable coating. The right materials to act as wicking agents include, but are not limited to, dioxide colloidal silicon, kaolin, titanium dioxide, silicon dioxide pyrogenic, alumina, niacinamide, sodium lauryl sulfate, low molecular weight polyvinylpyrrolidone, M-Pyrol, bentonite, magnesium aluminum silicate, Polyester, polyethylene Materials particularly suitable for purpose of this invention includes the wick effect agent no inflatable, examples of which are sodium lauryl sulfate, colloidal silicon, and low molecular weight polyvinylpyrrolidone.

The non-swelling solubilizing agents Preferred include (i) agents that inhibit crystalline formation of the pharmaceutical product or else acting through complexation with the same; (ii) an HLB micelle forming surfactant (hydrophilic-lipophilic balance) elevated, particularly anionic surfactants; (iii) citrate esters; Y combinations thereof, particularly combinations of complexing agents with anionic surfactants. Examples of agents that inhibit the crystalline formation of the product pharmacist or else they act by complexing with it includes polyvinyl pyrrolidone, polyethylene glycol (particularly PEG 8000), cyclodextrins?,?, And? And others modified cyclodextrins. Examples of surfactants forming raised HLB micelles include nonionic surfactants and / or anionics, such as Tween 20, Tween 60 or Tween 80; surfactants containing polyoxyethylene or polyethylene, or other surfactants long chain anionics, particularly sodium lauryl sulfate. Examples of citrate ester derivatives that are preferred are those alkyl esters, particularly triethyl citrate. They are especially effective combinations of these types of agents non-inflatable solubilizers. Preferred among such types of combinations are combinations of complexing agents and anionic surfactants. They are particularly preferred examples of such combinations polyvinylpyrrolidone with sodium lauryl sulfate and polyethylene glycol with sodium lauryl sulfate.

Lubricants are also added to ensure a proper tablet preparation, and these may include, but Not limited to: magnesium stearate, calcium stearate, acid stearic, polyethylene glycol, leucine, glyceryl behenate, and hydrogenated vegetable oil. These lubricants must be present in amounts from 0.1-10% (w / w), with a preferred range of 0.3 - 3.0% (w / w).

Preferred lubricants for the preparation of Tablets include but are not limited to sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, acid stearic, glycerol behenate, sodium lauryl sulfate, polyethylene glycol and hydrogenated vegetable oil. They are lubricants particularly preferred are those that are soluble in water or fluids gastric or easily emulsified. They are especially effective. combinations of lubricants. Lubricant combinations which are preferred are a small amount of hydrophobic lubricant with a greater amount of soluble or emulsifiable lubricant. Rate of use for lubricants ranges from 0.25 to 10.0% with a preferred range of 1 to 4%.

The administration system of the invention to provide a controlled release of any of a wide variety of therapeutically active agents. Examples include the following: antitussives, such as dextromethorphan hydrobromide and codeine; antihistamines such such as chlorpheniramine maleate, brompheniramine maleate, loratidine, astemizole, diclofenac sodium and terfenadine; decongestants such as pseudoephedrine and phenylephrine; antihypertensors such as nifedipine, verapamil, enalapril and salts thereof, metoprolol, metoprolol succinate, fumarate metoprolol, metoprolol tartarate; channel blockers of calcium such as verapamil, diltiazem, nifedipine, nimodipine, felodipine, nicardipine, isradipine and amlodipine; agents antidiabetics such as glipizide and ibromectin; inhibitors of proton pump such as omeprazole; H2 receptor antagonists such as cimetidine, ranitidine, famotidine, nizatidine; carbamazepine; Parkinson's agents such as selegiline, carbidopa / levodopa, pergolide, bromocriptine, amantadine, trihexyphenyl HCl; antiviral agents that include agents against herpesviruses such as acyclovir, famciclovir, foscarnet, ganciclovir; antiretroviral agents such as didanosine, stavudine, zalcitabine, zidovudine; and others such as amantadine, interferon alfa, ribavirin, rimantadine; and other agents therapeutic such as cimetidine, propiomazine, phenytoin, Tacrine, propolis, proplazam. The system of the present invention It is particularly applicable to therapeutic agents that are insoluble or poorly soluble in water or aqueous media at pH physiological.

In a preferred embodiment, the system of the present invention for dispensing nifedipine. In that preferred embodiment, the composition is free of agents that prevent solubilization of nifedipine such as group I metals and group II and salts thereof. In such compositions the agents Preferred osmotic are sugars.

Example 1 Granulation / tablet preparation / coating nifedipine

(TEC) or other suitable wetting agent is added to enough water to produce a good dispersion that It will atomize and pump well. Add between 50 to 100% of the PEG 8000. Next, add 50 to 100% of the nifedipine to the dispersion Finally add between 25 to 75% of the Cab-o-Sil® dispersion binder. Mix for ~ 20 minutes before spraying. Also, other components of the dispersion as necessary. Nor is a dispersion necessary, The binder can be a solution of PVP, PEG, sugar or other binder. The solution may be aqueous or organic. In some cases, a fusion granulation method may be preferred in hot. In this case, the binder can be a molten wax, a mixture of wax or other material.

Load a fluid bed tank with agents osmotic (xylitol, sorbitol, lactose, fructose, inositol, etc.). Add between 50 to 100% SLS, add the rest of PEG 8000, and add between 50 - 100% of the K-25 PVP, add all or the remaining amount of nifedipine and other components as require.

Spray the dispersion on the powder bed with a spray speed of 20 - 50 g / min that will produce granules of a suitable size for the preparation of tablets. (The spray rate will vary with the lot size). They adjust the inlet air flow rate and temperature for prevent the powder bed from becoming excessively granulated or becoming too wet (Normal range of 100 - 250 MCH and 40 - 60ºC, depending on the lot size).

Pour the granulation and add lauryl sulfate sodium (SLS), polyvinylpyrrolidone (PVP K-25), osmoagents, polyethylene glycol (PEG), nifedipine and Cab-o-Sil® (silicon dioxide colloidal; Cabot Corporation) remaining and mix in a machine V mixer or an appropriate mixer for 2-5 minutes or whatever is needed. Add a suitable lubricant such as magnesium stearate (approximately 0.5 - 1.5%) and combine for 2 - 5 minutes or whatever is necessary.

Pour the final combination from the mixer and prepare tablets in a suitable tablet preparation press. Coat the tablets in a tray coater or a fluid bed dryer with a spray rate of 30-100 g / min or more (depending on the batch size). The coating solution is prepared by dissolving 5% cellulose acetate, FN (National Form) in acetone or other suitable solvent and then adding 25-45% plasticizers such as TEC or PG or a mixture of the
same.

The procedure can also be performed. by direct compression, high shear granulation, dry compression or agitation.

In some cases it may also be desirable modify the solubility characteristics of osmoagents, solubilizers, granulation or other components to achieve desired release profile.

One method of modifying the release profile is to use a hydrophobic coating method. Initially, all components could be granulated together with 0-20% of PVP K25 or PEG 8000 or other aqueous or organic binder solution to ensure that the drug, sugars, and solubilizers are evenly distributed in all granules. Following this procedure, a coating agent such as hydrogenated castor oil, hydrogenated vegetable oil, type I, ethyl cellulose, glyceryl monostearate, Gelucire® or carnauba wax at 1-20% of the total weight of the formulation at 5 - could be applied 50% of the total granulation. The coating agent can be applied in a fluid bed by top spray, Wurster column coating, or rotor application; a tray coater equipped with a sieve for coating granules can also be used. The hydrophobic agent could be applied in a molten state or dissolved in a suitable solvent in which it would be sprayed onto the granules. Then both parts of the granulation, immediate and sustained release, could be perfectly combined, using a V-mixing machine before the preparation of
cousins

As an alternative, the method can be applied previously submitted to a component or combination of formulation components One or more can be granulated osmoagents alone or in combination with other osmoagents, solubilizers or other core components. So they can coat these granules alone or in combination with any other core component with the materials and methods described previously. Then the coated granules can be added to the rest of the formulation by dry combination, or, actually, can be granulated with the rest of the formulation.

Alternatively, a method of hydrophobic granulation In this method powder wax is mixed together with the part of the granulation to be coated (in them percentage intervals already indicated). Wax can be used not in powder by grinding the wax to a fine particle size. They can wax mixtures are formed by melting the wax, adding the component desired, allowing the mixture to thicken and sift or grind the wax mixture to a fine particle size. Then add the powdered wax or the wax mixture to the fluid bed with the part of the granulation to be coated. The granules are granulated materials increasing and controlling the inlet temperatures of the fluid bed (inlet temperature ~ 60-80 ° C, temperature output ~ 40-60 ° C), to cause the stages of fusion / thickening involved in the granulation process. In other examples it could be used to granulate a device with heating shirt. Here, however, the temperature ranges would apply to the substance used in the heating and cooling of the device, such as steam, water or oil hot.

For sustained release agents that are not waxes, the granulation procedure can be carried out using usual granulation techniques such as granulation aqueous wet or solvent granulation (in them percentage intervals already indicated). It can dissolve or the sustained release agent be suspended in the fluid of granulation or can be dispersed with the powders to be granulated. The granules are formed and dried and finally added to the rest of the formulation

Again, the techniques of granulation prior to a part of the entire formulation or to any component or mixture of components in the formulation. Then the sustained release granules can be combined with the rest of the formulation using techniques previously treated.

Finally, a technique of matrix. This technique involves adding a 5-30% powder wax. Total formulation weight, such as hydrogenated castor oil, Glyceryl Palmitoestearate, Glyceryl Behenate, Gelucire®, PEG 8000 or any other non-inflatable matrix forming agent known by someone skilled in the art to formulation. May granulate the wax with any component or combination of Components of the formulation with 0-20% PVP K25 or PEG 8000 u another binder solution, or a method of roller compaction or agitation in the formation of granules Then the granules are added to the rest of the formulation using the methods indicated above.

Then, the tablets can be prepared in tablets osmoagents, solubilizers or granulation agents of modified release, after the addition of a suitable lubricant. A single layer tablet has all the components of the formulation combined together and tablets. Can be provided one or more holes to give adequate release. They can provide one or more holes in the tablet. Can be it is beneficial for a tablet to have a hole on both sides of the tablet so that a release rate is achieved optimal One or more holes may be provided to achieve the desired release characteristics.

It is possible that any of the excipients discussed previously in combination with the tablet core may decrease the melting point. The temperatures at which you should expose the tablet in a coating procedure of aqueous color can be extreme enough (\60 °) as to partially melt the core and change the behavior Chemical physical of the tablet in solution or stability. For avoid this change, a color coating based on solvent at Shire Laboratories Inc., which consists of a mixture 1: 1 hydroxypropylcellulose and HPMC, and 1% of an aluminum lacquer colored dispersed in a 70:30 solution of IPA: water. Because The color coating is based on solvent, the temperature at that the tablets will be exposed in the procedure of coating is significantly lower (~ 35-40 ° C).

A delay of one to two may be beneficial hours before the start of dissolution. With the purpose of provide this time span a coating can be added sealed to the tablet. The sealed coating must provide a waterproof barrier for no more than two hours. Some polymers would provide this type of coating include ethyl cellulose, shellac, Eudragit RS. Others can be added components to the polymers in order to modify the coating to achieve the desired time span. A profit must be applied 1 - 10% weight to tablets. The coating is applied as an aqueous or organic solvent solution or a dispersion. Normally, the coating is applied on a tray cover or a fluid bed equipped with a column Wurster

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Example 2 Nifedipine formulations

The following are examples of formulations of the unique homogeneous composition within the tablet wall of the pharmaceutical form of the invention.

TABLE 1

Components 1A 1 B 1 C 1D 1E 1F 1G 1 HOUR Fructose 43.5 21.5 49.6 44.5 37.2 20.5 18.5 Lactose 315 17 18 17 17 17 32 17 17 Sorbitol 43.5 twenty-one twenty-one 19 PVPK25 fifteen fifteen fifteen 12.7 fifteen 12.5 fifteen 10 PEG8000 10 (5 *) 10 (5 *) 10 (5 *) 8.5 (4.2 *) 10 (5 *) 8.4 (4.2 *) 10 (5 *) 20 (10 *) TEC one* one* one* 1.7 * one* 0.84 * one* one* SLS 3 3 3 3 3 (1.5 *) 1.95 (1.25 *) 3 3 Cab-o-Sil® 2.0 (0.5 *) 1.0 (0.5 *) (0.5 *) 0.92 (0.42) 1 (0.5 *) 1.1 (0.4 *) 1 (0.5 *) 0.5 Nifedipine 8 * 8 * 8 * 6.8 * 8 * 6.7 8 * 8 * Stearate Mg 0.5 0.5 0.5 0.5 0.5 0.5 0.5 3 Sorbate K 3 Total 100 100 100 100 100 100 100 100 * Indicates in dispersion

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TABLE 2

Components 2A 2B 2 C 2D 2E Fructose Lactose 315 Sorbitol 15.5 15.5 5.5 23.25 12.5 Xylitol 23.25 23.25 23.25 15.5 6.5 Mannitol PVPK-12PF PVP-K25 35 35 35 35 fifty PEG8000 10 (5 *) 10 * 20 (10 *) 10 (5 *) 10 (5 *) SLS 5 5 5 5 10 Cab-o-Sil® 1 (0.5 *) 1 (0.5 *) 1 (0.5) 1 (0.5 *) Nifedipine 8.25 * 8.25 * 8.25 * 8.25 * 10 TEC one* one* one* one* Stearate Mg one one one one one Total 100 100 100 100 100 * Indicates in dispersion

TABLE 3

Components 3A 3B 3C 3D 3E 3F 3G 3H Fructose 21.5 20.5 19.5 16.5 18.5 17.5 17.5 16.5 Lactose 315 17 17 17 17 17 17 17 14.5 Sorbitol 2. 3 twenty-one 2. 3 twenty-one twenty-one twenty twenty 18.5 PVPK25 fifteen fifteen fifteen fifteen fifteen fifteen fifteen fifteen PEG8000 10 (5 *) 10 (5 *) 10 (5 *) 10 (5 *) 10 (5 *) 10 (5 *) 10 (5 *) 10 (5 *) TEC one* one* one* one* one* one* one* SLS 3 3 5 5 3 5 5 5 Cab-o-Sil® 1 (0.5 *) 1 (0.5 *) 1 (0.5 *) 1 (0.5 *) 1 (0.5 *) 1 (0.5 *) 1 (0.5 *) 1 (0.5 *) Nifedipine 8 * 8 * 8 * 8 * 8 * 8 * 8 * 8 * Stearate Mg 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Sorbate K 3 5 5 Glycerol 5 Cremophor HE** 5 Inositol 10 * Total 100 100 100 100 100 100 100 100 *  Dispersed Indica ** \ begin {minipage} [t] {155mm} Castor oil derivative with polyethylene glycol (other derivatives Suitable castor oil are described in the international Cosmetic Ingredient Dictionary - International Dictionary of Cosmetic Components- (5th Ed.), Cosmetic Fragrante and Toiletry Association - Association of Cosmetics, Fragrances and Toiletries. Washington, D.C. (1993), for example in pages 479-481) \ end {minipage}

TABLE 4

Components 4A 4B 4C 4D 4E 4F 4G 4H Fructose 13 13 4,5 17.5 18.5 15.25 15,675 15,675 Lactose 315 10.5 10.5 4 17 17.5 30 16.15 16.15 Sorbitol 16 16 6 twenty 22 19.95 19.95 PVPK25 35 fifteen 35 fifteen fifteen fifteen 14.25 14.25 PEG8000 10 (5 *) 35 (5 *) 35 (5 *) 10 (5 *) 10 (5 *) 10 9.5 9.5 (4.75 *) (4.75 *) TEC one* one* one* 6 * 0.95 * 0.95 * SLS 5 5 5 5 5 5 5 5

TABLE 4 (continued)

Components 4A 4B 4C 4D 4E 4F 4G 4H Cab-o-Sil® 1, (0.5 *) 1.0 (0.5 *) 1.0 (0.5 *) 1.0 (0.5 *) 1.0 (0.5 *) one 0.975 0.975 (0.475 *) (0.475 *) Nifedipine 8 * 8 * 8 * 8 * 8 * 8.25 7.6 * 7.6 * Stearate Mg 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Sorbate K 4.75 4.75 Glycerol 2.5 Cremophor HE 10 Inositol 5 Sulfate calcium 5 Total 100 100 100 100 100 100 100 100 * Indicates in dispersion

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TABLE 5

Components 5A 5B 5C 5 D 5E 5F 5G 5H Xylitol 15.5 5 32.5 31.5 24.0 16.9 twenty Sorbitol 15.0 5 15.5 15.5 fifteen 18.75 Fructose 7.5 17.5 Lactose 5 PEG8000 10 10 twenty 10 10 (5 *) 10 PVP-K25 35 35 fifteen fifteen 35 35 fifty 35 (5 *) TEC one one one 1.0 one* one* one* one* Cab-o-Sil® 1.0 one one 1 (0.5) 2 (1 *) 1 (0.5 *) 1 (0.5 *) Nifedipine 17 25 25 50.0 10 10 10.1 8.25 Stearate Mg 0.5 0.5 0.5 0.5 one one one one SLS 5.0 5 5 3 5 5 5 Sorbate K 3 Total 100 100 100 100 100 * Indicates in dispersion

TABLE 6

Formulations of nifedipine 6A 6B 6C 6D 6E 6F 6G 6H Xylitol 27.5 27.5 25.5 30.8 28.5 32.5 34.5 25.5 Sorbitol 25 25 26 28.5 29 30 30 26 SLS 5 5 4,5 4.8 5 5 5 4,5 PVP K25 15 (3 *) 15 (3 *) 13.5 (2.7 *) 14.2 (2.8 *) 15 (3 *) 15 (3 *) 5 13.5 Nifedipine fifteen fifteen 18 14.2 twenty fifteen 17.5 18 Acid stearic one eleven one one one one 2 one Stearate Mag. one one one one one one 0.5 one Cab-o-Sil® 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Behenate of glycerol 10 Acid stearic 5.0 (binder) Xylitol Coated with 10 5 acid stearic 6E coated with 10 acid stearic

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Example 3 Comparative percentage of nifedipine release

This example reports experiments that they compared the percentage of nifedipine released by some of the previous formulations in dosage administration forms of the invention compared to Procardia XL® (Pfizer, Inc .; 30 mg)

Materials and methods

Dosage administration forms of the invention in a Vankel dissolution apparatus containing synthetic gastric fluid without enzymes and undergo dissolution for 20 to 24 hours. Samples are periodically taken from the medium of solution and the concentration of nifedipine is analyzed by High performance liquid chromatography. The release calculated as a percentage against time. The dosage administration forms of the invention and tablets of procardia XL were evaluated in the same way to produce effective comparisons

Results

Figure 3 schematically shows both percent of nifedipine released by pharmaceutical forms of the invention containing the 1G formulations (30 mg); 1C (30 mg); as shown in table 1 compared to Procardia XL® (Pfizer, Inc .; 30 mg).

Figure 4 schematically shows both percent of nifedipine released by pharmaceutical forms of the invention containing formulations 2B (47 mg); 2C (47 mg); Y 2D (47 mg) as shown in table 2 compared to Procardia XL® (Pfizer, Inc .; 30 mg).

Figure 5 schematically shows both percent of nifedipine released by pharmaceutical forms of the invention containing the 3C formulations (30 mg); 3H (30 mg); as shown in table 3 compared to Procardia XL® (Pfizer, Inc .; 30 mg).

Figure 6 schematically shows both percent of nifedipine released by forms of the invention that contain the formulations 4H (30 mg); 4C (90 mg); as it shown in table 4 compared to Procardia XL® (Pfizer, Inc .; 30 mg)

Figure 7 schematically shows both percent of nifedipine released by forms of the invention that contain the 5G formulations (60 mg); 5H (60 mg); as it shown in table 5 compared to Procardia XL® (Pfizer, Inc .; 60 mg)

Figure 8 schematically shows both percent of nifedipine released by forms of the invention that contain the formulations 6E (60 mg); 6F (60 mg); as it shown in table 6 compared to Procardia XL® (Pfizer, Inc., New York; 60 mg)

Figure 9 schematically shows both percent of nifedipine released by forms of the invention that contain the 6F formulation (60 mg) with a sealed coating of 1% ethyl cellulose as shown in table 6 in comparison with Procardia XL® (Pfizer, Inc., New York; 60 mg).

Claims (19)

1. Osmotic administration system pharmaceutical comprising (a) a semipermeable wall that maintains its integrity during the pharmaceutical administration and that has the less a passage through it; and (b) a single composition homogeneous within said wall, composition containing (i) a pharmaceutical agent, (ii) at least one non-solubilizing agent inflatable that increases the solubility of the pharmaceutical agent; (iii) at least one non-inflatable osmotic agent and (iv) an effect agent non-inflatable wick scattered throughout the composition, being free said composition of a swelling polymer. 2. Pharmaceutical administration system according to claim 1, wherein the solubilizing agent does not inflatable is selected from the group consisting of (i) agents of complexation; (ii) an HLB micelle forming surfactant high; (iii) citrate esters; and (iv) combinations of the same. 3. Pharmaceutical administration system according to claim 2, comprising the combination of at least a complexing agent with at least one anionic surfactant. 4. Pharmaceutical administration system according to claim 1, wherein the wicking agent is select from the group consisting of sodium lauryl sulfate, dioxide of colloidal silicon and low weight polyvinylpyrrolidone molecular. 5. Pharmaceutical administration system according to claim 1, wherein the semipermeable wall It comprises cellulose acetate and triethyl citrate. 6. Pharmaceutical administration system according to claim 1, wherein the solubilizing agent is select from the group consisting of sodium lauryl sulfate and a polyvinylpyrrolidone. 7. Pharmaceutical administration system according to claim 1, wherein the pharmaceutical agent has a limited aqueous solubility at physiological pH. 8. Pharmaceutical administration system according to claim 7, wherein the pharmaceutical agent is nifedi-
Pine tree. 9. Pharmaceutical administration system according to claim 1, wherein the composition within said wall also comprises a lubricant. 10. Pharmaceutical administration system according to claim 1, wherein the pharmaceutical agent is release through said at least one passage. 11. Pharmaceutical administration system according to claim 1, wherein the at least one osmotic agent Non inflatable is a sugar. 12. Pharmaceutical administration system according to claim 11, wherein the sugar is not more than ten rings 13. Pharmaceutical administration system according to claim 12, wherein the sugar has no more than Five rings 14. Pharmaceutical administration system according to claim 13, wherein the sugar is selected from group consisting of monosaccharides, disaccharides and trisaccharides. 15. Pharmaceutical administration system according to claim 14, wherein the osmotic agent is Select from xylitol and sorbitol. 16. Pharmaceutical administration system according to claim 1, wherein said pharmaceutical agent is select from antitussives, antihistamines, decongestants, antihypertensors, calcium channel blockers, agents antidiabetics, proton pump inhibitors, antagonists of H2 receptor, carbamazepine, agents against Parkinson's, and agents antivirals 17. Pharmaceutical administration system according to claim 1, wherein said pharmaceutical agent is select dextromethorphan hydrobromide, codeine, maleate Chlorpheniramine, Brompheniramine Maleate, Loratidine, Astemizole, diclofenac sodium, terfenadine, pseudoephedrine, phenylephrine, nifedipine, verapamil, enalapril, metoprolol, succinate metoprolol, metoprolol fumarate, metoprolol tartarate, verapamil, diltiazem, nimodipine, felodipine, nicardipine, isradipine, amlodipine, glipizide, ibromectin, omeprazole, cimetidine, ranitidine, famotidine, nizatidine, carbamazepine, selegiline, carbidopa / levodopa, pergolide, bromocriptine, amantadine, acyclovir, famciclovir, foscarnet, ganciclovir, didanosine, stavudine, zalcitabine, zidovudine, amantadine, interferon alfa, ribavirin, rimantadine, propiomazine, phenytoin, Tacrine, propolis and proplazam. 18. Pharmaceutical administration system according to claim 1, wherein the pharmaceutical agent is Select from glipizide, omeprazole and nifedipine. 19. Pharmaceutical administration system according to claim 1, wherein the pharmaceutical agent is glyph
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